Phase I - double digits (<100)
Phase II - Triple digits (<300)
Phase III - quadruple digits, also C being the 3rd letter of the alphabet, phase III trials 'compare' efficacy -> RCTs. (<3000)
3. Phamacokinetic testing to determine ADME characteristics (absorption, distribution, metabolism and elimination)
Phase 3 = 1000-3000 to confirm effectiveness, monitor side effects and compare with other treatments. (⭐therapeutic confirmation - Randomized controlled trials; efficacy, safety)
[!INFO] Mmemonic: Bag of flowers
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- Isolated systolic hypertension is the predominant form of hypertension in the elderly population.
- develops as a result of the reduced elasticity of the arterial system.
- commonly seen among the elderly as there is increased deposition of calcium and collagen to the arterial wall
- most common cause of blindness in young men
++ /dev/null
- **Tau protein** is a protein which stabilizes microtubules and regulates protein binding to microtubules in healthy cells.
[!INFO] Tau causes Tangles; APP causes Plaques
- Reprogramming of stem cells to differentiate into a cell type that is more suitable to cope with the new stresses than the original cell type at that location. Can occur in epithileal OR mesenchyal cells.
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- Disorderly, but non neoplastic proliferation.
Other causes of subtotal villous atrophy
- Cyst is the infective stage. (Cysts are immediately infectious upon excretion, they can survive chlorinated water)
- Cyst are ingested via contaminated water or food (like salads). Faeco-oral person to person transmission can occur (eg. Child care centers)
- Abdominal pain, watery diarrhea, weight loss.
- Severe infection can invade the mucosa in severe infection but usually there is no invasion.
- Treatment: tinidazol, ⭐metronidazole is second line due to concern of side effects. Achieves parasite clearance within 1 week.
- AL amyloidosis <- The most common form.
Other types of amyloidosis:
- See Source
- One example : Dialysis related amyloidosis -> (Aβ2M) Dialysis-related amyloidosis; the precursor proteins is β-2 microglobulin.
[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.
[!INFO] Once the presense of amyloid is found
the precursor protein must be determined.
(Both (AL and AA) have the beta pleted sheet structure) (Harrison's - page 804)
[!INFO] AL Amyloidosis and mutliple myeloma are closely related but NOT the same.
- In AL amyloidosis, free light chains are secreted in excess by a small plasma cell clone population in the bone marrow without evidence of multiple myeloma (in AL amyloidosis, there are <10% malignant plasma cells in bone marrow) Source
- To diagnose multiple myeloma >10% of bone marrow aspirate cells should be plasma cells. Source
- 10% of myeloma patients of multiple myeloma patients (mostly those who produced lambda light chains)
- Most frequent sites of AL deposition are the kidneys, heart, peripheral nerves, gastrointestinal tract, and liver
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Source
Pharmacological efficacy (also called Intrinsic efficacy) is
[[2018-OCT-BSQ#Pulmonary vascular resistance]]
- But ⭐80% of NALFD patients have normal liver enzymes. Source
Pathophysiology of NAFLD
Insulin resistance is the key prerequisite for NAFLD.
- ⭐Steatosis (fatty change), Hepatitis (inflammation) and Fibrosis
- Starts with fat accumulation in centrilobular areas and then spreads outwards. The liver will be soft, yellow and greasy. (i.e starts in ZONE 3)
- Steatosis is ⭐macrovessicular.
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!
- Hepatocyte ballooning with necrosis
- Intracellular eosinophilic includions: ⭐Mallory Denk bodies
- ⭐Neutrophil infiltration to remove the necrotic hepatocytes and those with Mallory Denk bodies.
Fibrosis
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- Also appears in zone 3 and spread outwards. (⭐central vein sclerosis)
- Perisinusoidal scarring in space of disse also similarly spreads outwards. [[HepaticSinusoidSpaceOfDisse.jpg]]
- These changes cause ⭐micronodular cirrhosis. (aka Laennec cirrhosis)
- Mild increases in ALT and AST with ALT > AST; mild elevation of ⭐gamma-GT. (don't be mislead into thinking it's alcoholic hepatitis)
- Elastography - to evaluate degree of fibrosis.
- Absolute mainstay of treatment: Lifestyle advice aimed at weight loss with exercise and dieting.
- Orlistat (enteric lipase inhibitor) is used as adjunct in severely obese to reduce intestinal lipid absorption
- Can cause vitamin malabsorption.
- Pioglitazone has been proven to reduce NASH but weight gain CCF, bladder cancer and fracture risk are increased.
Source
- Dyslipidaemia (Low HDL and high TGL)